Germline mutational dynamics in myotonic dystrophy type 1 males

  title={Germline mutational dynamics in myotonic dystrophy type 1 males},
  author={Loreto Martorell and Josep G{\'a}mez and Mar{\'i}a Luisa Cayuela and F K Gould and John P McAbney and Tetsuo Ashizawa and Darren G. Monckton and Montserrat Baiget},
  pages={269 - 274}
Background: The CTG repeat expansion causing myotonic dystrophy type 1 is unstable in the germline, and frequent intergenerational length changes are observed, giving rise to the unusual genetics of the disorder. The repeat is also somatically unstable, and expanded alleles accumulate throughout life, thus compromising simple measures of intergenerational stability. Objective: To gain a better understanding of the intergenerational dynamics of the DM1 repeat in the male germline. Methods: We… 

Figures from this paper

Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity.

Using single-molecule PCR, data establish a primary role for somatic instability in DM1 severity and show that the level of instability is highly heritable, implying a role for individual-specific trans-acting genetic modifiers.

DMPK hypermethylation in sperm cells of myotonic dystrophy type 1 patients

Assessing DNA methylation upstream to the CTG expansion in motile sperm cells of four DM1 patients, together with availability of human embryonic stem cell (hESCs) lines with paternally inherited hypermethylated expansions, excludes the possibility that DMPK hypermethylation leads to selection against viable sperm cells (as indicated by motility) inDM1 patients.

Molecular genetics of congenital myotonic dystrophy

Replacement of the myotonic dystrophy type 1 CTG repeat with ‘non-CTG repeat’ insertions in specific tissues

This study has characterised a novel mutation configuration at the DM1 CTG repeat that arose as somatic mosaicism in a juvenile onset DM1 patient with a non-expanded allele of (CTG)12 and tissue specific expansions ranging from ( CTG)1100 to 6000.

Chemotherapeutic deletion of CTG repeats in lymphoblast cells from DM1 patients.

Three lymphoblast cell lines derived from two DM1 patients treated with either ethylmethanesulfonate (EMS), mitomycin C, mitoxantrone or doxorubicin, at therapeutic concentrations, accumulated deletions following treatment with potential mechanisms of drug-induced deletion are presented.

Dynamic DNA and human disease : mathematical modelling and statistical inference for myotonic dystrophy type 1 and Huntington disease

New mathematical models are developed by modifying a previously proposed stochastic birth process to incorporate possible contraction and reveal, for the first time, that the expansion bias observed in the distributions of repeat lengths is likely to be the cumulative effect of many expansion and contraction events.

Myotonic Dystrophy Type 1 (DM1): From the Genetics to Molecular Mechanisms

STR instability is an important and unique form of mutation that is linked to >40 neurological, neurodegenerative, and neuromuscular disorders, and in particular, abnormal expansion of trinucleotide repeats have been associated with different diseases.

Myotonic dystrophy types 1 and 2.



Complex patterns of male germline instability and somatic mosaicism in myotonic dystrophy type 1

It is confirmed that the male germline mutational pathway is distinct from that of the soma, but the extent of variation is highly variable from one individual to another and not obviously correlated with progenitor allele length.

Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analyses.

Detailed analysis of intergenerational 'reductions' paternally transmitted to two offspring suggests that some apparent reductions may be artifacts of somatic expansion in the parent, as well as suggesting that large contractions, including reversions into the normal size range, are restricted to the germline.

Gonosomal mosaicism in myotonic dystrophy patients: involvement of mitotic events in (CTG)n repeat variation and selection against extreme expansion in sperm.

It is concluded that DM patients can be considered gonosomal mosaics, i.e., combined somatic and germ-line tissue mosaics because of the length distributions of intermediate- or small-sized alleles in fathers' sperm were significantly different from that in their offspring's blood.

Somatic instability of CTG repeat in myotonic dystrophy

It is concluded that somatic instability of the CTG repeat may cause substantial tissue variability of theCTG repeat size in adult-onset DM, providing a potential mechanism for the variable pleiotropism.

Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy

The isolation of an expressed sequence is reported from this region which detects a DNA fragment that is larger in affected individuals than in normal siblings or unaffected controls, and it is postulated that this unstable DNA sequence is the molecular feature that underlies DM.

Postzygotic instability of the myotonic dystrophy p[AGC]n repeat supported by larger expansions in muscle and reduced amplifications in sperm

Evidence of an early postzygotic instability of the [AGC] repeat in DM is provided, with Skeletal muscle showed a larger repeat number than leucocytes in the same patient.

Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy.

It is concluded that intergenerational contractions of the CTG repeat in leukocyte DNA frequently accompanies apparent anticipation, especially when DM is maternally transmitted, and the paternal origin of the repeat and the presence of therepeat contraction in a sibling increase the probability of theCTG repeat contraction.

Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic mutation mechanism.

A statistical model based on incomplete processing of Okazaki fragments during DNA replication was found to provide an excellent fit to the data but variation in parameter values among individuals suggests that the molecular mechanism might be more complex.

Anticipation in myotonic dystrophy

The data suggest that the expansion of the GCT repeats plays an important role in anticipation although other factors, including the sex of the affected parent, may have significant effects on molecular mechanisms of anticipation.

Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice

The results show that Msh2 is required for somatic instability of the HD CAG repeat, suggesting important functional correlations between repeat length and pathology.